The rostral ventromedial medulla (RVM), with its projections to the dorsal horn, constitutes the efferent component of a pain-control system that descends from the brain to the spinal cord. Considerable evidence has emerged regarding participation of this system in persistent pain conditions such as inflammation and neuropathy. The role of this brain region in mediating the analgesic effects of opiates such as morphine is well known. The RVM normally exerts an inhibitory influence on dorsal horn neurons However, persistent noxious stimulation triggers dynamic, time-related alterations in RVM synaptic activity. In inflammatory pain models, descending facilitation transiently increases reducing the net effect of inhibition. Over time, descending inhibition increases resulting in decreased nocifensive behavior. After nerve injury, RVM plasticity leads to facilitation of spinal cord nociceptive output, exacerbation of primary hyperalgesia and enhanced sensory input from adjacent regions (secondary hyperalgesia). AMPA receptor activation in the RVM has been shown to inhibit spinal nociceptive transmission and nocifensive behavior. Increased AMPA receptor function in the RVM is implicated in the activity-dependent plasticity that occurs in response to persistent pain produced by tissue inflammation. Targeting and synaptic clustering of AMPA receptors is essential for efficient excitatory transmission. NP1 is a member of the pentraxin family of proteins that is expressed exclusively in neurons and facilitates AMPA receptor clustering. Given the postulated role of NP1 in excitatory synaptic transmission and the role of AMPA receptor systems in pain processing, we have used gene deletion and viral-mediated transfer techniques to examine whether manipulations that target this protein can affect the expression of persistent pain. To investigate the role of NP1 in inflammatory pain, we quantified pain-related behavior in wildtype and NP1 knock out mice following intraplantar formalin injection;an animal model of tonic pain resulting from tissue injury. This test is characterized by two phases of pain behavior: an early phase caused by direct activation of peripheral nociceptors (05 min after injection) and a late phase (1540 min after injection) which reflects early central hypersensitivity. Mice lacking the gene encoding NP1 exhibited significantly greater nocifensive behavior in the late phase of the formalin test relative to wildtypes. However, neither early phase behavior nor basal nociceptive thresholds were altered suggesting that lack of NP1 specifically exacerbates inflammatory hypersensitivity induced by intraplantar formalin. Immunohistochemistry revealed a marked induction of NP1 in the RVM within 20 min after formalin injection. Significant induction was still apparent two hours after injection. To determine whether NP1 expression in the RVM is involved in the descending modulation of nociception, we generated a series of lentiviral vectors to enable region-specific silencing or over-expression of the NP1 protein. Silencing NP1 expression in the RVM of rats significantly potentiated formalin-evoked nocifensive behaviors, consistent with an obligatory role of NP1 in the RVM in the descending inhibition of tonic pain. Our studies also suggest that targeting this protein is effective in the treatment of neuropathic pain. Pain after nerve injury has long been explained by increased excitability of primary afferents and sensitization of dorsal horn nociceptive circuits. However, more recent studies have revealed that descending facilitatory influences from the RVM are critical for the maintenance of experimental neuropathic pain . To determine the contribution of NP1 to nerve-injury evoked pain, we assessed mechanical hypersensitivity in wild type and NP1 knock out mice following spared nerve injury. Nerve injury led to marked mechanical hypersensitivity of the injured limb. This enhanced nociception is significantly inhibited in NP1 knockout mice. In order to probe the specific involvement of RVM NP1 in mediating the attenuated response of NP1 knockout mice, we infused a lentiviral vector which drives expression of functional NP1 protein directly into the RVM. Selective rescue of RVM NP1 expression in knockout mice restores allodynia produced by nerve injury. Consistent with the data obtained in NP1 knockout mice, silencing NP1 expression in the RVM of rats prior to nerve injury inhibits allodynia. Furthermore, it decreases mechanical hyperalgesia. These findings are consistent with the observation that descending facilitatory systems arising in the RVM are necessary for the maintenance of neuropathic pain and identify NP1 in the RVM as a critical element in the descending facilitation of nerve-injury evoked pain. Together, these data suggest that targeting NP1 may be a novel therapeutic strategy for reversing persistent pain of diverse etiologies. On-going studies are examining the role of NP1 in other conditions of perisistent pain including those associated with diabetes and AIDS antiretroviral therapy. The role of other members of the pentraxin family in pain modulation is currently being assessed.